Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro and in vivo

Journal Article · Sun Jun 01 04:00:00 EDT 2014 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2014.03.013· OSTI ID:22439725

Wang, Lijuan ^[1]; Wang, Changyuan ^[1]; Peng, Jinyong ^[1]; Liu, Qi ^[1]; Meng, Qiang ^[1]; Sun, Huijun ^[1]; Huo, Xiaokui ^[1]; others, and

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1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, Liaoning (China)

The purpose of this study was to investigate the enhancing effect of dioscin on the absorption of methotrexate (MTX) and clarify the molecular mechanism involved in vivo and in vitro. Dioscin increased MTX chemosensitivity and transepithelial flux in the absorptive direction, significantly inhibiting multidrug resistance 1 (MDR1) mRNA and protein expression and MDR1 promoter and nuclear factor κ-B (NF-κB) activities in Caco-2 cells. Moreover, inhibitor κB-α (IκB-α) degradation was inhibited by dioscin. Dioscin enhanced the intracellular concentration of MTX by down-regulating MDR1 expression through a mechanism that involves NF-κB signaling pathway inhibition in Caco-2 cells. Dioscin strengthened MTX absorption by inhibiting MDR1 expression in rat intestine. In addition, even though MTX is absorbed into the enterocytes, there was no increase in toxicity observed, and that, in fact, decreased toxicity was seen. - Highlights: • Dioscin raised MTX concentration by inhibiting MDR1 in Caco-2 cells. • Dioscin suppresses MDR1 by inhibiting NF-κB signaling pathway in Caco-2 cells. • Dioscin can enhance MTX absorption via inhibiting MDR1 in vivo and in vitro. • Dioscin did not increase MTX-induced gastrointestinal mucosal toxicity.

• OSTI ID: 22439725
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 277; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ATP
BROMIDES
CARCINOMAS
DOXORUBICIN
EOSIN
HEMATOXYLIN
IN VITRO
IN VIVO
KETONES
LARGE INTESTINE
MESSENGER-RNA
METHOTREXATE
MONITORING
PERMEABILITY
PHOSPHORYLATION
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RATS
TOXICITY